Encapsulation of lipophilic ingredients in dispensible spray dried powders suitable for inhalation

ABSTRACT

A method of manufacturing a flowable and dispersible powder includes solubilizing a lipophilic substance in a terpene to form a mixture and treating the mixture to form a nanoemulsion dispersed in an aqueous solution. The aqueous solution includes at least one functional excipient. The nanoemulsion is then spray dried, thereby evaporating first the aqueous portion and then the terpene to form a dry powder formed from solid particles comprising the lipophilic substance.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a non-provisional of U.S. Provisional ApplicationNo. 62/280,968, filed on Jan. 20, 2016, the complete disclosure of whichis herein incorporated by reference.

BACKGROUND OF THE INVENTION

Due to their hydrophobic nature and low solubility in water, lipophilicactive substances often exhibit poor bioavailability via the oralgastrointestinal (GI) delivery route. Furthermore, accurate and precisedosing is poor for drugs delivered via the GI system due to inherentvariability caused by factors such as fasting state and first passmetabolism. As an alternative, pulmonary delivery using a dry powderinhaler (DPI) may be used. Traditional lactose-carrier (lactose blend)formulations for DPIs typically offer low drug loads, commonly less than6% (wt/wt), and low delivery efficiencies (DE), typically delivering<30% of the drug to the lungs. Lactose blends are also highly flow ratedependent, showing significant variability with respect to aerodynamicperformance. Once formulated, lactose blends rely on inter-particleforces to bind micronized drug to larger lactose carrier particles tomaintain a uniform distribution of drug. This can present challengesduring transportation and filling of powder into packages, which impartmechanical energy capable of redistributing or otherwise disturbingblend uniformity.

Engineered particles (e.g. spray dried) for DPIs offer significantimprovements in drug payload, DE, good aerosol performance across a wideflow rates, and a lower risk for segregation of drug from excipients.However, lipophilic drug substances are challenging to encapsulate intodry, flowable, and dispersible powders that are compatible with drypowder inhalers. In addition, oils and fats exhibit poor dissolution anddispersion when incorporated into aqueous systems which are common inthe preparation of annex solutions used to produce spray dried powders.This invention relates to new uses for terpenes as non-toxic, naturalsolubilizers for preparing vehicles (or annex solutions) which may thenbe spray dried to produce powders comprising various drugs, agriculturalchemicals, cosmetics, and foods.

BRIEF SUMMARY OF THE INVENTION

The present disclosure generally relates to dry powder compositions andmethods for administering and preparing such compositions. Embodimentsare directed to dry powder compositions in which volatile terpenes areused as processing aids to create nanoemulsions containing lipophilicactive substances, which may then be stabilized in dry powder form, andto methods for preparing and using such compounds. One group of suchlipophilic active substance are extracts of cannabis, which arecommercially available as sticky, resinous oils, or as high puritycrystalline forms. The dry powder compositions may include any suitablelipophilic substance. For example, there may be an oil-in-waternanoemulsion composition that includes cannabinoids in the oil fractionthat is spray dried to form a dry powder composition. The oil-in-wateremulsion compositions may include a hydrophobic amino acid, e.g.leucine, a disaccharide, e.g. trehalose, and/or an oligosaccharide, e.g.inulin. Such dry powder compositions may be administered to a subjectvia pulmonary inhalation.

In one aspect, a method of manufacturing a flowable and dispersiblepowder is provided. The method may include solubilizing a lipophilicsubstance in a terpene to form a mixture and treating the mixture toform a nanoemulsion dispersed in an aqueous solution. The aqueoussolution may include at least one functional excipient. The terpenefraction may include at least one functional excipient. The method mayalso include spraying drying the nanoemulsion, thereby evaporating atleast a portion of the terpene and the majority of the water to form asuitable dry powder formed from solid particles that include thelipophilic substance.

In another aspect, a method of manufacturing a flowable and dispersiblepowder includes dissolving a lipophilic ingredient in an organic solventto form a lipophilic phase and dissolving at least one of a surfactantor an emulsifier in the lipophilic phase. The method may also includedissolving one or more excipients into water to form an aqueous phaseand chilling the aqueous phase to between about 1° C. and 10° C. Themethod may further include dispersing the lipophilic phase into thechilled aqueous phase to form an emulsion that includes nanosized oildroplets. Alternatively, the emulsion may be prepared by heating theorganic and aqueous phases to between 50 and 75° C. The method mayinclude spray drying the emulsion to form a dry powder that includes oneor more lipophilic ingredients.

In another aspect, a method of manufacturing a flowable and dispersiblepowder may include mixing an oil solution with a water solution to forman oil-in-water emulsion composition. The oil solution may include acannabinoid. The method may also include spray drying the oil-in-wateremulsion composition to form a dry powder composition.

In another aspect, a dry powder composition is provided. The dry powdercomposition may include a lipophilic component and one or more of ahydrophobic amino acid, a disaccharide, a oligosaccharide, a surfactant,an emulsifier, a stabilizing additive, or a bulking agent. The drypowder composition may have bulk density between 0.05 and 0.30 g/cm³,tap density between 0.10 and 0.60 g/cm³, and moisture content belowabout 10% w/w. The dry powder composition may also include between about0.01% and 60% w/w of the lipophilic component.

In another aspect, a method of aerosolizing a dry powder formulation isprovided. The method may include providing a dry powder formulation thathas a lipophilic component and one or more of a hydrophobic amino acid,a disaccharide, a oligosaccharide, a surfactant, an emulsifier, astabilizing additive, or a bulking agent. The dry powder composition mayinclude between about 0.01% and 50% w/w of the lipophilic component. Themethod may also include introducing the dry powder formulation to anaerosolization device and introducing the dry powder formulation to agas stream within the aerosolization device to disperse the dry powderformulation.

The features and advantages of the present invention will be apparent tothose skilled in the art. While numerous changes may be made by thoseskilled in the art, such changes are within the spirit of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flowchart depicting a process for manufacturing a flowableand dispersible powder according to embodiments.

FIG. 2 is a flowchart depicting a process for manufacturing a flowableand dispersible powder according to embodiments.

FIG. 3 is a flowchart depicting a process for manufacturing a flowableand dispersible powder according to embodiments.

FIG. 4 depicts a schematic of an annex solution that was prepared forspray drying according to embodiments.

FIG. 5 depicts a graph of a droplet size distribution after processinginto a nanosized oil-in-water emulsion according to embodiments.

FIG. 6 is a plot of an optical particle size distribution of powdersspray dried for pulmonary delivery according to embodiments.

FIG. 7 is a scanning electron microscopy image of spray dried particlescontaining cannabinoids according to embodiments.

FIG. 8 is a plot of an optical particle size distribution of powdersspray dried for pulmonary delivery according to embodiments.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention relate to dry powder compositionsfor improved pulmonary, topical, enteral, or parenteral delivery oflipophilic substances, and to methods for the preparation and use ofsuch compositions. More particularly, volatile terpenes are employed asprocessing aids to achieve dispersion of the lipophilic fraction(s) in ananoemulsion which is stabilized and encapsulated in functionalexcipients using a spray drying method. Treatment with nano-sized unitsof lipophilic drug substances has shown enhanced bioavailability invivo, as described in T. Yi, J. Wan, H. Xu, X. Yang. A new solidself-microemulsifying formulation prepared by spray-drying to improvethe oral bioavailability of poorly water soluble drugs. European Journalof Pharmaceutics and Biopharmaceutics, Volume 70, Issue 2, October 2008,Pages 439-444 and in S. Gupta, R. Kesarla, A. Omri. FormulationStrategies to Improve the Bioavailability of Poorly Absorbed Drugs withSpecial Emphasis on Self-Emulsifying Systems. ISRN Pharmaceutics,December 2013, the entire contents of which are hereby incorporated byreference. The increase in surface area to volume with decreasingparticle size results in greater potential for efficient transport anduptake in the human body. Such lipophilic dry powder compositions may beadministered to a subject via pulmonary inhalation in an amounteffective to treat and/or prevent a number of conditions, such assystemic and/or lung conditions.

An inhalable dry powder preparation for lipophilic drug substancesoffers advantages over oral GI delivery. For example, pulmonary deliveryoffers a high surface area with rapid absorption due to highvascularization and circumvention of the first pass effect, as describedin Sung, J. C.; Pulliam, B. L.; Edwards, D. A. Nanoparticles for drugdelivery to the lungs. Trends in Biotechnology. 2007, 25, 563-570, theentire contents of which is hereby incorporated by reference. Rapid drugabsorption may be favorable in analgesic, antiemetic, and othermedicaments. Further, powder compositions may be engineered such that acontrolled fraction of the dose impacts the deep lung (fine particlefraction) while the remainder impacts mucosa in the upper airways. Sucha delivery method results in rapid uptake via the lung followed by aslow, sustained release of drug via GI and transmucosal modes. By thesemeans, pharmacokinetics of the product may be modulated.

A formulation and a spray drying technique are used to stabilizelipophilic active ingredients in a dry powder having good flowproperties and dispersibility. The lipophilic ingredients aresolubilized and/or diluted in carrier terpene(s) and the combinedmixture is treated to form a nanoemulsion dispersed in an aqueoussolution. The aqueous fraction contains dissolved functional excipientswhich serve as bulking, encapsulation, stabilizing, and flow enhancementagents. During the spray drying process the aqueous and terpene carrierphases evaporate to form solid particles. The resulting powders exhibitexcellent dispersibility into aerosol suitable for pulmonary delivery.Dissolution of powders into aqueous liquids produces a nano-sizeddispersion of the oil phase. Such methods have proven to be veryefficient, stable, and exhibit excellent batch to batch consistency.

Lipophilic ingredients, such as cannabinoid extracts, are commonlyavailable as sticky, viscous concentrates which present processingchallenges for discretization into more desirable nano-sized particles.Dissolving these challenging drug substances in solvents reduces surfacetension and enables their break up into nano-sized droplets via highshear mechanisms such as ultrasonics or microfluidizers. The inclusionof surfactant in the oil phase stabilizes nano-sized droplets in anemulsion by acting as a barrier against droplet coalescence, therebyenhancing emulsion stability. Formulating with excipients having lowaqueous solubility (e.g. leucine), the nano-sized sticky oil phase isencapsulated within a shell which precipitates first during the dryingevent. This entrapment produces particles having surface characteristicswhich are dominated by the encapsulating excipient. Use of leucine as anencapsulating excipient has been shown to impart excellent flowabilityand dispersibility to powders. Cannabinoids are a class of compoundsderived from Cannabis plants. At least 113 cannabinoids have beenidentified in the plant, as described in O. Aizpurua-Olaizola, U.Soydaner, E. Öztürk, et al. Evolution of the Cannabinoid and TerpeneContent during the Growth of Cannabis sativa Plants from DifferentChemotypes. J. Nat. Prod., 2016, 79 (2), pp 324-331, the entire contentsof which is hereby incorporated by reference. The two primarycannabinoids contained in Cannabis are Δ9-tetrahydrocannabinol (THC):

and cannabidiol (CBD):

Commonly used recreationally, cannabinoids are being used and studiedfor use in a number of medical conditions including, but not limited to,epilepsy, refractory epilepsy, fragile X syndrome, osteoarthritis,anxiety, chronic pain. Other medical uses may include the treatment ofsleep disorders including insomnia, fibromyalgia, spinal injury, phantomlimbs, migraines and/or other headaches, cramps, sleep apnea, cancer,muscular dystrophy, HIV/AIDS, glaucoma, hypertension, fatigue, asthma,ALS, lack of appetite, anorexia, cachexia, gastrointestinal disorders,nausea, diabetes, Crohn's, anxiety, ADD/ADHD, stress, bipolar disorder,obsessive compulsive disorder (OCD), post-traumatic stress disorder(PTSD), depression, Tourette's, seizures (including Dravet Syndrome),multiple sclerosis, Alzheimer's, Parkinson's, spasticity, osteoporosis,inflammation, arthritis, sexual performance and libido enhancement,and/or symptoms thereof.

While largely discussed in relation to cannabinoid compositions, it willbe appreciated that compositions containing other lipophilic drugsubstances may be manufactured and/or administered using the methodsdescribed herein. Examples of other lipophilic/low solubility drugsubstances include, but are not limited to, those shown in Table 1below.

TABLE 1 Lipophilic/low solubility drug substances Drug Solubility(ug/ml) Class Alpha tocopherol 0.007 tocopherol Amphotericin B 82aminoglycoside Atorvastatin 0.5 statin Azithromycin 514 azalide(macrolide antibiotic) Beclomethasone 2.1 glucocorticoid Budesonide 46glucocorticoid Caspofungin 367 echinocandin Ciprofloxacin 1350fluoroquinoline Clemastine 0.4 antihistamine Clofazimine 1.5 leprostaticCyclosporine 5 immunosuppressant Dihydroergotamine 229 ergot alkaloidDronabinol 2.6 cannabinoid Dutasteride 0.9 5alpha reductase inhibitorsErithromycin 459 macrolide antibiotic Felodipine 7.1 calcium channelblocker Fentanyl 24 opiate Flecainide 32 sodium channel blockerFluticasone furoate 43.4 glucocorticoid Fluticasone proprionate 11.4glucocorticoid Furosemide 118 loop diuretic Glycopyrronium 0.95 LAMAIndacaterol 8 LABA Itraconazole 9.6 triazole Loxapine 103 tricyclicantipsychotic Mometasone 5.2 glucocorticoid Nimodipine 12 calciumchannel blocker Tacrolimus 4 macrolide immunosuppressant Tretinoin 4.8retinoid Vilanterol 11.8 LABA

In one embodiment, a composition of the present disclosure is a drypowder that includes cannabinoids. As used herein, the term cannabinoidsincludes natural derivatives of cannabis or hemp plant, or synthesizedanalogues. As used herein, the term “dry” means that the composition hasa moisture content such that micron-size particles are readilydispersible in an inhalation device to form an aerosol, while largerparticles exhibit good flow properties. In some embodiments, thismoisture content may be below about 10% by weight water, below about 7%by weight water, below about 5% by weight water or below about 3% byweight water. Furthermore, as used herein, the term “inhalation powder”means a composition that includes finely dispersed solid particles thatare capable of being readily dispersed in an inhalation device andsubsequently inhaled by a subject so that the particles reach the lungsto permit penetration into the upper and lower airways. Thus, the powderis said to be “respirable.” In some embodiments, a dry powdercomposition of the present disclosure may have a tap density greaterthan about 0.1 g/cm³, greater than about 0.20 g/cm³ or greater thanabout 0.4 g/cm³ and mass median aerodynamic diameter (MMAD) between 1and 4 μm. While cannabinoids may be predominately used in thedescriptions contained in this disclosure, it should be understood thatthe present disclosure may be practiced with any other substantiallylipophilic active and low solubility drug substances (such as thosedisclosed in Table 1 above), and derivatives and analogues thereof,among other things, to treat various respiratory and systemicconditions.

In certain specific embodiments, a dry powder composition of the presentdisclosure comprises cannabinoids present in an amount of between about1% and 30%, in some cases between about 4% and 15%, and still in othercases about 12% by weight of the composition, the powder having a tapdensity between about 0.1 g/cm³ and 0.3 g/cm³. The dry powdercompositions may further include leucine in an amount of between about10% and 90%, trehalose or inulin of between about 1% and 60%, andsurfactant of between about 0.1% and 10% by weight of the composition.In some cases, the dry powder compositions may further include leucinein an amount of between about 40% and 70%, trehalose or inulin ofbetween about 20% and 50%, surfactant of between about 0.1% and 5% byweight of the composition. In still other cases, the dry powdercompositions may further include leucine in an amount of about 60%,trehalose or inulin in the amount of about 20%, surfactant in the amountof about 1.5% by weight of the composition. In some embodiments,particles of a dry powder composition may have an average particle sizeof less than or equal to about 10 micrometers (μm) in diameter asdefined by the MMAD. In some embodiments, at least 95% of the particleshave a MMAD of less than about 10 μm. In some embodiments, the diametermay be less than or equal to about 7 μm. In other embodiments, thediameter may be less than or equal to about 5 μm. In certain specificembodiments, the diameter may be between about 0.5 μm and about 5 μm indiameter, particularly between about 1 μm to about 3 μm. Dry powdercompositions of the present disclosure that include particles having anaverage particle size of less than or equal to about 5 μm in diametermay be particularly useful for delivery via an oral inhalation device.In the case of cannabinoids, advantages of pulmonary delivery via DPIapproach include rapid absorption similar to smoking or vaporizing butwithout the health risks associated with these traditional forms ofinhaled delivery. Additional advantages include DE's greater than 60%and high dose precision. Aerodynamic properties of a number of powderbatches according to the present invention are shown in Tables 2 and 3below.

TABLE 2 Mean values (n = 3) for physical and aerodynamic properties(Anderson Cascade Impactor and Plastiape RS01 inhaler) of select powderbatches containing oily extracts [GSD—geometric standard deviation;FPF—fine particle fraction (powder mass recovered on plates 2 to 7 +powder mass recovered on filter)/(mass emitted from capsule − residualpowder mass on inhaler)] Oil Extract Bulk Tap (% Density Density D₅₀MMAD ED FPF DE Batch Id wt/wt) (g/mm³) (g/mm³) (um) (um) GSD (%) (%) (%)P20150828-2 6.4 0.12 x 2.1 3.4 1.5 82 82 67 P20150828-3 6.4 0.13 x 1.92.9 1.8 78 93 72 P20170105-1 7.5 0.12 x 2.2 2.8 1.6 90 95 85 P20170105-26.6 0.20 x 2.0 3.3 1.6 86 85 73 P20161222-7 7.4 0.12 x 2.2 2.7 1.8 88 8878 P20160611-1 12.0 0.06 0.11 1.9 2.4 1.9 95 85 81 P20160611-3 12.3 0.060.12 2.2 2.3 2.1 97 93 90 P20160611-7 18.4 0.09 0.16 2.6 3.5 2.0 99 6464

TABLE 3 Mean values (n = 3) for aerodynamic properties (Anderson CascadeImpactor and Plastiape RS01 inhaler) of batch P20161222-7 tested at twostandard flow rates. Flow Rate MMAD ED FPF DE (lpm) (um) GSD (%) (%) (%)28.3 3.43 1.45 82 82 67 60 2.92 1.77 78 93 72

In other embodiments, a dry powder composition of the present disclosuremay comprise particles having an average particle size of greater thanor equal to about 10 μm in diameter as defined by MMAD (measured usingcascade impaction). In some embodiments, at least 95% of the particleshave a MMAD of greater than about 10 μm. In certain specificembodiments, the particle size may be between about 10 μm and about 50μm in diameter, particularly about 20 μm to about 40 μm. Dry powdercompositions of the present disclosure that include particles having anaverage particle size of greater than or equal to about 10 μm indiameter may be particularly useful for nasal delivery or for oral soliddosage forms, or as preparations intended to enhance stability of theactive component.

In other embodiments, a dry powder composition may include particleshaving a broader range, having approximately 90% of the particlesbetween 1 to about 12 μm. This range of particle sizes may be useful forsimultaneous delivery of actives to the lungs and upper airways via anoral inhalation device. For example, the finer particles impact the deeplung while the larger particles impact mucosa in the upper airways,resulting in rapid uptake via the lung followed by a slow, sustainedrelease of drug via GI and transmucosal modes. Specifically, a controlof size fractions present in a bimodal and/or broad monomodaldistribution would allow for control over pharmacokinetic profile.Active lipophilic substances delivered to the lungs would be morerapidly absorbed into the bloodstream, while the fraction deposited onthe upper airways would be absorbed more slowly, similar to theabsorption of oral solid dosages. This could prospectively result in afast-acting drug (short Tmax) with sustained drug activity (longhalf-life).

In some embodiments, the particles may be hollow. In some embodiments,the particles may be porous, having a sponge-like appearance. In someembodiments, the particles may have a spheroidal shape distribution,which may be relatively uniform. In other embodiments the particles arecorrugated, appearing as wrinkled raisins. In cannabinoid embodiments,the potency as measured by select cannabinoid concentration iseffectively unchanged when compared to the unformulated drug (i.e.within 10% of the unformulated drug).

Administration of an effective amount of a cannabinoid composition,including tetrahydrocannabinol (THC), tetrahydrocannabinolic acid(THCa), cannabidiol (CBD), cannabidiolic acid (CBDa), cannabinol (CBN),cannabichromene (CBC), cannabigerol (CBG) and others, of the presentdisclosure may be particularly useful in treating conditions including,but not limited to, pain, cancer, HIV, seizures, spasticity, multiplesclerosis, muscular dystrophy, Parkinson's, Tourette syndrome,Huntington's disease, Alzheimer's, glaucoma, anxiety, anorexia,cachexia, PTSD, OCD, inflammation, insomnia, arthritis, lupus,neurodegenerative diseases, and sexual performance disorders.

When heated during smoking or vaping, cannabinoid acids such as THCa andCBDa decarboxylate to form THC and CBD. Due to the relatively lowtemperatures employed in the spray drying process (i.e. <80° C.),production of powders containing cannabinoid acids (e.g. THCa, CBDa) ofinterest would be feasible.

In cannabinoid embodiments, suitable forms of lipophilic drug substancesinclude oils, resins, and crystals which may be used to formulate drypowder products. These drug substances may be produced by any number ofcommercially available methods including solvent (e.g. butane, propane,hexane) and supercritical extraction (e.g. CO₂). The resultant drugsubstances may be comprised of 40-99.9% cannabinoids. Syntheticcannabinoids, such as the THC MARINOL® (dronabinol), may also beincluded.

In some embodiments, in addition to lipophilic drugs, a composition ofthe present disclosure may further include one or more additives. Oneexample of a suitable additive is a hydrophobic amino acid. Suchhydrophobic amino acids may include, but are not limited to, tryptophan,tyrosine, leucine, dileucine, trileucine and phenylalanine. In someembodiments, it may be desirable to include a hydrophobic amino acid ina lipophilic composition so as to improve the physical stability and/ordispersibility of the composition, to improve the chemical stability ofcannabinoids and/or to alter the taste of the composition by masking thebitter taste of cannabinoids, and/or to alter the rate the compositionis absorbed into the systemic circulation from the lung (e.g., increaseor slow the rate of absorption). While not wishing to be bound to anyparticular theory, it is currently believed that the hydrophobic aminoacid additive remains on the surface of the particles and protects themfrom moisture and light, thereby increasing the stability of theformulation.

Another suitable additive may be a cellulose based polymer and/or apolymeric agent used to modify surface properties. Such polymeric agentsmay include, but are not limited to, hyaluronic acid,polyethyleneglycol, hydroxypropylmethylcellulose (HPMC) andmethylcellulose (MC). In some lipophilic dry powder embodiments, it maybe desirable to include cellulose based polymers to improve the physicalstability, powder handling, and/or dispersibility of the composition, toimprove the chemical stability, and/or to alter the rate the compositionis absorbed into the systemic circulation from the lung (e.g., increaseor slow the rate). While not wishing to be bound to any particulartheory, it is currently believed that the cellulose based polymeradditive remains on the surface of the particles and protects them frommoisture and light, thereby increasing the stability of the formulation.

Another example of a suitable additive is a carbohydrate bulking agent.Such carbohydrate bulking agents may include, but are not limited to,lactose, mannitol, trehalose, raffinose, and maltodextrins. In someembodiments, it may be desirable to include a carbohydrate bulking agentin a composition of the present disclosure so as to improve the physicalstability of the composition. Furthermore, in some embodiments, thecarbohydrate bulking agent may also improve the chemical stability ofcannabinoids or lipophilic substances.

Another suitable additive is a volatile terpene. Such terpenes mayinclude, but are not limited to, d-limonene, other grades of limonene,and beta-myrcene. Naturally occurring and refined cannabinoid substancesmay contain over 100 terpenes, as described in Turner C. E., M. A.Elsohly and E. G. Boeren, 1980. Constituents of Cannabis sativa L. XVII.A review of the natural constituents. Journal of Natural Products 43(2): 169-234 and in R. Brenneisen, M. A ElSohly. Marijuana and theCannabinoids, Chapter 2, p. 28, the entire contents of which are herebyincorporated by reference. In some embodiments, it may be desirable toinclude additional terpenes to aid in the processing of viscouslipophilic active substances into nanometer sized droplets dispersed inan aqueous phase prior to powder production via spray drying. The activelipophilic substance is dissolved into the terpene and then sequentiallyprocessed into nano/micrometer scale oil in water emulsions usinghomogenizers (e.g. Ultra-Turrax, IKA) or ultrasonic methods (e.g.Sonifier, Branson). Further refinement into nanometer scale (D₅₀ of 0.1to 0.5 μm) oil-in-water emulsions is accomplished using ultrasonic (e.g.Sonifier, Branson) and/or high shear (e.g. M110Y, Microfluidics)equipment operated according to common practiced methods. In someembodiments, it may be desirable to incorporate surfactant(s) into theactive oil/terpene mixture to stabilize emulsion droplet size duringprocessing. While not wishing to be bound to any particular theory, itis currently believed that, like water, the terpenes are largelyfugitive during the spray drying process and that residual addedterpenes used for processing are minimal in the dried powdercompositions. It will be apparent to experts in the field that the useof other fugitive or volatile elements is not restricted to terpenes andthat other volatiles may be contemplated.

Surfactants and/or emulsifiers may be used to stabilize theactive/solvent phase as an oil in water emulsion having nanometer sizeddroplets. Examples of stabilizing additives include non-ionicdetergents, nonionic block copolymers, ionic surfactants, phospholipids(including DSPC), citrates (including sodium citrate and dylaurylcitrate), polysorbates, sorbitan laurate, polyglyceryl-4 laurate, andcyclic oligosaccharides (e.g. alphadextrin and beta-cyclodextrin). Otheradditives known to those of ordinary skill in the art may also beincluded.

Generally, additives suitable for use in the compositions of the presentdisclosure may be included in an amount of about 99% or less by weightof the dry powder composition, 90% or less by weight of the composition,or 75% or less by weight of the composition. In other embodiments,additives suitable for use in the compositions of the present disclosuremay be included in an amount of from about 75% to about 99% by weight ofthe composition. In other embodiments, additives suitable for use in thecompositions of the present disclosure may be included in an amount offrom about 10% to about 20% by weight of the composition.

The compositions of the present disclosure may further includepharmaceutically acceptable auxiliary substances or adjuvants,including, without limitation, pH adjusting and buffering agents and/ortonicity adjusting agents, such as, for example, citrate, sodiumacetate, sodium lactate, sodium chloride, potassium chloride, calciumchloride, etc. Similarly, the compositions of the present disclosure maycontain pharmaceutically or nutritionally acceptable carriers andexcipients including microspheres, microcapsules, nanoparticles or thelike.

In certain embodiments, the dry powder composition may be reconstitutedand the resulting reconstituted powder may have a pH greater than 3.0,preferably greater than 3.5 and most preferably greater than 4.0.Reconstitution may be done by introducing a solvent, such as water or anacidic compound, to the dry powder composition to form the reconstitutedformulation. This formulation may be usable with liquid aerosolizers,nebulizers, injectables (e.g. parenteral, intradermal, subcutaneous,intramuscular, intraosseous, intraperitoneal, intravenous) oral liquiddosage forms (e.g. syrup, oral suspension, oral solution, oral drop,oral emulsion, mixture, linctuse, elixir), and/or other administrationtechniques.

An inhalation powder composition of the present disclosure may bedelivered to a subject by any means so long as the solid particles ofthe dry powder composition are capable of being inhaled by a subject sothat the particles reach the lungs to permit penetration into the upperand lower airways. In certain embodiments, a dry powder composition ofthe present disclosure may be delivered to a subject by placing the drypowder within a suitable dosage receptacle in a sufficient amount.Suitable dosage receptacles include those used in reservoir devices(e.g., devices that contain more than one dose in which the deviceitself meters the dose) or factory-metered dose devices (e.g., devicesin which each dose is contained in either a single unit or multipleunits). In one example, a suitable reservoir device may have a dosagereceptacle that fits within a suitable inhalation device to allow forthe aerosolization of the dry powder composition by dispersion into agas stream to form an aerosol and then delivering the aerosol soproduced from a mouthpiece attached for subsequent inhalation by asubject in need of treatment. Such a dosage receptacle includes anycontainer enclosing the composition known in the art such hydroxypropylmethyl cellulose or polymer capsules with a removable portion or bodythat can be cut or pierced that allows dispersal of the dry powdercomposition (e.g., via a gas stream directed into the container and viacentrifugal force). Such containers are exemplified by those shown inU.S. Pat. Nos. 4,227,522, 4,192,309, and 4,105,027, the entire contentsof which are hereby incorporated by reference.

Suitable containers also include those used in conjunction withPlastiape's RS series of inhalers, GlaxoSmithKline's Ventolin Rotahalerbrand powder inhaler and/or Fisons' Spinhaler brand powder inhaler.Another suitable unit-dose container which provides a superior moisturebarrier is formed from an aluminum foil plastic laminate. The powdercomposition is filled by weight or by volume into the depression in theformable foil and hermetically sealed with a covering foil-plasticlaminate. Such a container for use with a powder inhalation device isdescribed in U.S. Pat. No. 4,778,054 and is used with GlaxoSmithKline'sDiskhaler (U.S. Pat. Nos. 4,627,432; 4,811,731; and 5,035,237), theentire contents of which are hereby incorporated by reference. Anothersuch container and powder inhalation device including a vibratingmechanism is described in U.S. Pat. No. 9,132,246, the entire contentsof which are hereby incorporated by reference. Yet another suitabledelivery system would be a single use disposable device where the drypowder is pre-packaged within the device. In other embodiments, a drypowder composition of the present disclosure may be delivered to asubject via a tracheal tube.

In some embodiments, compositions of the present disclosure may beprepared by spray drying an oil-in-water emulsion containingcannabinoids or other lipophilic ingredients and pharmaceuticallyacceptable carrier(s) under conditions sufficient to provide arespirable dry powder composition. In some embodiments, the dry powdercomposition is substantially amorphous.

Dry powder formulations are often prepared by spray drying. Spray dryingof the formulations is carried out, for example, as described in the“Spray Drying Handbook”, 5^(th) ed., K. Masters, John Wiley & Sons,Inc., NY, N.Y. (1991) and in Platz, R. et al., U.S. Pat. No. 6,592,904,the entire contents of which are hereby incorporated by reference.Generally speaking, spray drying is a process in which a mixture,suspension, or hybrid of soluble and insoluble ingredients andexcipients is atomized via a nozzle to form fine droplets which areintroduced into and mixed with a hot gas or other fluid stream. For theatomization process, methods such as rotary atomization, pressureatomization and two-fluid atomization can be used. Examples of suitabledevices are disclosed in U.S. Pat. No. 6,372,258, the entire contents ofwhich are hereby incorporated by reference. The mixture prepared forspray drying, or annex solution, may be an emulsion, a solution,suspension, slurry, or the like, but care must be taken such that itsconstituents uniformly distributed and, ultimately, the powderedcomposition. Preferably the aqueous mixture is a solution. In someembodiments, the aqueous mixture may have a solids content of at least1% by weight water. In other embodiments, the aqueous mixture may have asolids content of at least 2% by weight water. In other embodiments, theaqueous mixture may have a solids content of at least 4% by weightwater. The solvents, water, and terpenes, evaporate from the dropletsproducing a dry powder containing the lipophilic ingredient and anyexcipients. The powder is pneumatically conveyed via ducts from thedrying chamber to a collection system where it is separated from thedrying gas stream. Suitable powder collection systems include bag housetype filters, cyclones, and electrostatic separators.

In some embodiments, the spray drying is done under conditions thatresult in a substantially amorphous powder of homogeneous constitutionhaving a particle size that is respirable, has a low moisture content,and has characteristics that allow for ready aerosolization. In someembodiments, the particle size of the resulting powder is such that morethan about 95% of the mass is in particles having a diameter of about 10μm or less. Powder production by spray drying may be scaled-up from labto pilot-scale batch sizes. The process can produce up to kilogramquantities of powder per day at high yield (>80%) and with no loss inpurity and little to no loss in potency (<5%).

By increasing the percentage of solids in the annex solution(nanoemulsion), other dry powder cannabinoid compositions suitable fororal delivery forms, incorporation into edibles, or for long termstorage at room temperature, can be produced at high yields (85-99%) byspray drying, or more preferably by granulation. Such powders exhibitexcellent chemical stability and good flow properties. The opticalparticle size distribution for such powders is in the 5-100 μm range.Ingredients suitable for producing a 100 g batch of such a powder mayinclude, for example, leucine (8 g), trehalose (70 g), d-limonene (48g), DSPC (3.5 g), citrate (0.5 g) supercritically extracted cannabis oilcontaining 30% CBD (or another lipophilic substance) (18 g), and water(400 g).

In some embodiments, dry powder compositions may be prepared by otherprocesses such as lyophilization and jet milling as disclosed in WO91/16038, the entire disclosure of which is hereby incorporated byreference. A number of formulation and processing strategies may beuseful to improve, among other things, the storage and stabilityproperties of the dry powder cannabinoid compositions of the presentdisclosure. In certain embodiments, the cannabinoids used may be chosento be of a higher purity. In other embodiments, steps may be taken toavoid oxidation of cannabinoids. For example, processing and packagingof the composition may be performed under argon or nitrogen. Similarly,in some embodiments the processing and packaging may be performed tominimize exposure to direct light. Such steps may reduce light-mediateddegradation of cannabinoids. In some embodiments, steps such as postspray drying treatment in a vacuum oven may be taken to reduce theamount of moisture or residual terpenes in the composition. Such stepsmay be useful to avoid hydrolysis, deamidation, and/or oxidation ofcannabinoids or other lipophilic actives. As mentioned above, acarbohydrate bulking agent or encapsulation additives may be added tothe composition, which also may improve chemical stability.

Furthermore, while the dry powder lipophilic drug substance compositionsof the present disclosure have many advantageous properties in certainembodiments. One particularly advantageous property is that thecompositions may have a pharmacokinetic profile that is favorable fortreatments where rapid uptake and rapid onset of effect is desirableand/or where a prolonged high concentration of drug in the lung orbloodstream is preferable. Advantages in the in vivo pharmacokineticprofiles of cannabinoids, e.g. CBD, THC, CBN, as described in theexamples given in this invention, whereby referring to a specificcannabinoid, may be assumed to be similarly advantageous for othercannabinoids.

For example, in certain cannabinoid embodiments, therapeutic value(plasma concentrations of between approximately 10 and 200 ng/mL) isachieved within 4 to 8 minutes after administration via inhalation. Themaximum concentration of THC-COOH (Tmax) may be less than or equal toabout 30 minutes, less than or equal to about one hour, or less than orequal to about six hours. In some embodiments, median Tmax may bebetween about three minutes and three hours. Similarly, in certainembodiments, the median amount of time necessary for blood plasma levelsof a subject to decrease to one half of the total maximum concentrationof THC-COOH (T_(1/2)) may be greater than two hours. In someembodiments, T_(1/2) may be about three hours.

In certain embodiments, upon administration of a dry powder THCcomposition to a subject, the mean maximum blood plasma concentration ofTHC-COOH (Cmax) may be within the range of about 50% to about 150% ofabout n×70 ng/mL, wherein n represents a factor to be multiplied and maybe a value from 0.01 to 10 and when n=1, the dose is 1 mg.

In one particular embodiment, a dry powder composition having THCpresent in an amount of about 1 mg may provide a mean maximum bloodplasma concentration of THC-COOH within the range of about 50% to about150% of about 70 ng/mL as measured following a single pulmonaryadministration. As would be recognized by one of skill in the art, fordry powder compositions containing lower or higher concentrations of THCthan 1 mg, the above ranges may be adjusted directly proportionally bythe dose. Accordingly, in certain embodiments the present disclosurealso provides compositions where the THC or other cannabinoid is presentin the dry powder composition in an amount of about n×1 mg. The drypowder composition provides a mean maximum blood plasma concentration ofTHC-COOH (Cmax) within the range of about 50% to about 150% of aboutn×70 ng/mL. The maximum blood plasma concentration of THC-COOH ismeasured following a single pulmonary administration of the dry powdercomposition where n represents a factor to be multiplied and may be avalue from 0.01 to 10.

In some embodiments, the dry powder cannabinoid compositions of thepresent disclosure may provide average delivery efficiencies (DEs)(ED*FPF) between 40% and 90%. In other embodiments, the dry powdercannabinoid compositions of the present disclosure may provide averagedelivery efficiencies between 70% and 90%. Delivery efficiency is theemitted dose (ED) (%) (i.e., the amount of the dry powder that exits theinhaler as a percentage of the initial amount of the dry powder presentin the capsule) multiplied by the fine particle fraction (%) (i.e.,respirable amount or the amount of the dry powder having a MMAD of 5.8μm or less as a percentage of the emitted dose). In other words, ED isequivalent to (powder mass packaged in capsule—residual powder mass incapsule after actuation—residual powder mass on inhaler)/(powder masspackaged in capsule).

In some embodiments, the dry powder cannabinoid compositions of thepresent disclosure may provide a bioavailability of 40% or more.Bioavailability is herein defined fraction of a packaged dose of drugthat reaches the systemic circulation by either pulmonary, mucosal, orgastrointestinal absorption.

Compositions of the present disclosure may be administered to a subjectvia pulmonary administration in an amount effective to achieve thedesired cannabinoid concentration in the blood. Administration of aneffective amount of a composition of the present disclosure may beuseful in pharmaceutical, medicinal, and recreational cannabisapplications.

As will be recognized by one of ordinary skill in the art, the effectiveamount needed to treat a particular condition or disease state willdepend on the individual, the condition, length of treatment, theregularity of treatment, the type of cannabinoid(s) used, and otherfactors, but can be readily determined by one of ordinary skill. Thepatient can achieve a desired dosage by inhaling or otherwiseadministering an appropriate amount of the composition.

FIG. 1 depicts a flowchart of a process 100 for manufacturing a flowableand dispersible powder. At block 102, the process 100 may includesolubilizing a lipophilic substance in a terpene or other organicsolvent to form a mixture. The lipophilic substance may include acannabinoid, budesonide, ciclesonide, cyclosporine, fluticasone,formoterol, mometasone furoate, mycophenolate, rapamycin, salmeterol,tacrolimus, tiotropium, vilanterol trifenatate, and/or derivatives oranalogues thereof. Possible cannabinoids include, without limitation,tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCa),cannabidiol (CBD), cannabidiolic acid (CBDa), cannabinol (CBN),cannabichromene (CBC), and/or cannabigerol (CBG). At least onefunctional excipient may be added to water to form an aqueous solutionat block 104. The mixture may be dispersed into the aqueous solutionusing a homogenizer or ultrasonic device at block 106 to form a coarseemulsion. The coarse emulsion may then mixture may then be treated withan ultrasonic or high shear device at block 108 to help form theemulsion with nano-sized oil particles. The terpene may help thelipophilic substance form nano-sized oil droplets in the emulsion. Theterpene may include d-limonene, other limonenes, beta-myrcene, and/orother terpenes. In some embodiments, the aqueous solution may include atleast one functional excipient. Functional excipients may include, forexample, hydrophobic amino acid, a disaccharide, an oligosaccharide, asurfactant, an emulsifier, a stabilizing additive, and/or a bulkingagent. The nanoemulsion may be spray dried at block 110, therebyevaporating at least a portion of the terpene and substantially all ofthe water to form a dry powder formed from solid particles that includethe lipophilic substance. As used herein, substantially all may meanthat at least 93% of the water is evaporated, in some cases at least 96%of the water is evaporated, and in other cases at least 98% of the wateris evaporated. Such dry powder may be administered using a dry powderinhaler and/or be reconstituted for use in other administrationtechniques.

In some embodiments, the dry powder composition may have a moisturecontent below about 10% by weight water, with a preferred range between1 and 6%. The dry powder composition may include between about 0.1% and30% by weight of cannabinoid component. The dry powder composition mayhave a tap density between about 0.1 g/cm and 0.4 g/cm. In someembodiments, the dry powder composition may include a hydrophobic aminoacid, a disaccharide, a oligosaccharide, a surfactant, an emulsifier, astabilizing additive, and/or a bulking agent. The hydrophobic amino acidmay include tryptophan, tyrosine, leucine, dileucine, trileucine, and/orphenylalanine. Surface modifying and flow enhancing agents may includehyaluronic acid, polyethyleneglycol, hydroxypropylmethylcellulose(HPMC), and/or methylcellulose (MC). In other embodiments, the bulkingagent may include lactose, mannitol, trehalose, raffinose, and/ormaltodextrins. In some embodiments, the stabilizing additive includes anon-ionic detergent, a nonionic block copolymer, an ionic surfactant,phospholipids, citrates, polysorbates, sorbitan laurate, polyglyceryl-4laurate, and/or cyclic oligosaccharisdes.

FIG. 2 shows a flowchart of a process 200 of manufacturing a flowableand dispersible powder. Process 200 may be similar to process 100, andmay include similar steps and include similar chemical components. Atblock 202, process 200 may include dissolving a lipophilic ingredient inan organic solvent to form a lipophilic phase. The lipophilic ingredientmay include one or more of a cannabinoid (which may be a naturallyderived cannabinoid a synthetically derived cannabinoid, and/or acombination thereof), budesonide, ciclesonide, cyclosporine,fluticasone, formoterol, mometasone furoate, mycophenolate, rapamycin,salmeterol, tacrolimus, tiotropium, vilanterol trifenatate, and/orderivatives or analogues thereof. The lipophilic ingredient may also, oralternatively, include an extract of hops, an extract of sage (Salviaofficinalis/lavandulaefolia), rosmarinic acid, a polyphenolic compound,caffeic acid, and/or nicotine. In some embodiments, the lipophilicingredient includes at least two of the above substances. In someembodiments, each of the lipophilic substances is encapsulated in aunique domain, while in other embodiments, the multiple lipophilicsubstances are encapsulated in domains as a mixture. Improved deliveryefficiency of combination therapeutics may be possible with the approachpresented herein. It may also present a new pathway to repurposeexisting drugs or offer new processing options to address pastformulation problems. Optionally, formulating combination products inthis manner could enable multiple drugs (dual, triple, and so on) to beprocessed in separate lipophilic fractions which may limit or preventdegradation due to chemical incompatibility. In cases where lipophilicand hydrophilic combinations are desired, the respective fractions maybe formulated and spray dried to produce a single particle of thecombination drugs. Still in other cases an insoluble or sparinglysoluble micronized drug could be introduced to the lipophilic fractionto segregate it from chemically incompatible active or inactivecomponents. Examples of combination products (two or more APIs) includeCombivent Respimat® (albuterol+ipratropium), Advair Diskus®(fluticasone+salmeterol), Symbicort HFA® (budesonide+formoterol),Utibron™ Neohaler® (indacaterol+glycopyrronium), and Flutiform®(fluticasone propionate+formoterol fumarate). The organic solvent mayinclude a terpene, such as d-limonene, other limonenes, and/orbeta-myrcene. Other organic solvents may include an alcohol such asethanol or methanol. In some embodiments, the lipophilic ingredient iscombined with the organic solvent in a ratio of less than 1.0 by weight.

At block 204, at least one of a surfactant or an emulsifier is dissolvedin the lipophilic phase. Emulsifiers may include non-ionic detergents,nonionic block copolymers, ionic surfactants, and/or combinationsthereof. Other emulsifiers may include phospholipids, polysorbates,sorbitan laurate, polyglyceryl-4 laurate, dylauryl citrate, and/orcombinations thereof. In some embodiments, the emulsifier may include acyclic oligosaccharide, such as an alphadextrin and/orbeta-cyclodextrin. At block 206, one or more excipients are dissolvedinto water to form an aqueous phase. Stability of the nanoemulsion maybe enhanced by adjustments to pH by the introduction excipients such ascitrate or sodium citrate. The lipophilic phase is dispersed intotheaqueous phase at block 208 to form an emulsion that includesnano-sized oil droplets. This dispersing may include the use ofultrasonic homogenization and/or high pressure/high shearhomogenization. In some embodiments, the emulsion may be formed in acontinuous, inline manner such that emulsifiers are not required. Suchan emulsion may be rapidly fed into a spray dryer. The nanosizeddroplets have a droplet size d₅₀ between about 20 nm and 1 μm, a dropletsize d₅₀ between about 20 and 500 nm, or a droplet size d₅₀ betweenabout 50 and 300 nm.

The emulsion may include a matrix forming excipient. Matrix formingexcipients may include an oligosaccharide, such as inulin. In someembodiments, the matrix forming excipients include a saccharide and/or apolysaccharide. The emulsion may further include an encapsulatingexcipient, such as an amino acid like leucine.

The emulsion may be spray dried to form a dry powder that includes thelipophilic ingredient at block 210. The emulsion may also be sonifiedwith an ultrasonic horn operating in pulse mode. Droplets formed duringthe spray drying may be atomized using a multi-fluid atomizer and atleast one fluid utilized by the multi-fluid atomizer may be a compressedgas. In some embodiments, the dry powder includes between about 0.01%and 50% w/w of the lipophilic ingredient.

FIG. 3 depicts a flowchart of a process 300 of manufacturing a flowableand dispersible powder, similar to processes 100 and 200 describedabove. Process 300 may include mixing an oil solution with a watersolution (or other solvent) to form an oil-in-water emulsion compositionat block 302. The oil solution may include a cannabinoid or otherlipophilic ingredient. The oil-in-water emulsion composition may includeat least one of a hydrophobic amino acid, a disaccharide, and/or aoligosaccharide. The oil-in-water emulsion composition may be spraydried to form a dry powder composition at block 304. This dry powdercomposition may be administered, such as by pulmonary inhalation, in thetreatment of a number of systemic and/or lung conditions.

To facilitate a better understanding of the present invention, thefollowing examples of certain aspects of some embodiments are given. Inno way should the following examples be read to limit, or define, theentire scope of the invention. Additionally, the processes formanufacture and administration of the dry powder compositions describedherein may include additional steps, have steps omitted, and/or stepscombined.

EXAMPLE 1

An annex solution (feedstock) for spray drying into dry powder wasprepared in two portions: a lipophilic phase preparation and an aqueousphase preparation. The preparation of the lipophilic phase involveddissolving a lipophilic active ingredient (hops oil extract) into anorganic solvent (d-limonene) followed by dissolving a surfactant(emulsifier) into the lipophilic/solvent mixture. The aqueous phasepreparation involved selecting excipients (e.g. amino acids,carbohydrates, disaccharides, oligosaccharides, cellulose) anddissolving these excipients into water at or near 20° C., or at highertemperatures depending on excipient solubility.

The lipophilic phase preparation was dispersed into the aqueous phasepreparation to form an emulsion 400 that includes nanosized oil droplets402 distributed within aqueous phase preparation 404 as shown in FIG. 4.The majority of oil droplets 402 ranged between about 0.01 nm and 0.3nm. The particle size distribution for the oil droplets 402 asdetermined by Malvern Mastersizer 3000 with HydroMV is shown in FIG. 5.The particle size distribution included the following values: D₁₀(um)=0.103; D₅₀ (um)=0.205; and D₉₀ (um)=0.453. The emulsion containingnano-particles was formed using common practices such as ultrasonicand/or high pressure homogenizer techniques. The resultant annexsolution was spray dried into dry powder which had D₁₀ (um)=1.0; D₅₀(um)=2.2; and D₉₀ (um)=4.1. Capsules filled with powder (10 mg target)were aerosol tested (ACI at 28.3 lpm) with the RS01 inhaler were foundto have MMAD (um)=3.3, FPF=85%, and DE=73%.

“Active substances” or “active ingredient” as described herein includesa lipophilic agent, drug, compound, composition of matter or mixturethereof which provides some pharmacological, nutraceutical, ornutritional action.

EXAMPLE 2

As in Example 1, an annex solution (feedstock) for spray drying into drypowder was prepared in two portions: a lipophilic phase preparation andan aqueous phase preparation. The preparation of the lipophilic phaseinvolved dissolving a lipophilic active ingredient into an organicsolvent followed by adding a surfactant (emulsifier) into thelipophilic/solvent mixture. The aqueous phase preparation involvedselecting excipients (e.g. amino acids, carbohydrates, disaccharides,oligosaccharides, cellulose, acids) and dissolving these excipients intowater at or near 20° C., or at higher temperatures depending onexcipient solubility.

The aqueous and lipophilic preparations were heated to between about 60°C. and 70° C. The lipophilic phase preparation was then dispersed intothe aqueous phase preparation to form an emulsion 400 that includesnanosized oil droplets 402 distributed within aqueous phase preparation404. The majority of oil droplets 402 ranged between about 0.01 nm and0.3 nm. The droplet size distribution as measured by Malvern Mastersizer3000 with HydroMV included the following values: D₁₀ (um)=0.2; D₅₀(um)=0.3; and D₉₀ (um)=0.5. The emulsion containing nano-particles wasformed using common practices such as ultrasonic and/or high pressurehomogenizer techniques. The resultant annex solution was spray driedinto a dry powder (7.5% oil extract content) which had D₁₀ (um)=0.8; D₅₀(um)=2.0; and D₉₀ (um)=4.0. Capsules filled with powder (10 mg target)were aerosol tested (ACI at 28.3 lpm) with the RS01 inhaler hadMMAD(um)=2.5, FPF=95%, and DE=89%.

“Active substances” or “active ingredient” as described herein includesa lipophilic agent, drug, compound, composition of matter or mixturethereof which provides some pharmacological, nutraceutical, ornutritional action.

EXAMPLE 3

Dry powder cannabinoid compositions suitable for pulmonary delivery wereproduced using a spray dryer at high yield (80-90%) and at 5 g batchsizes. These powders exhibited very good aerosol performance whenactuated via the RS01 inhaler (Plastiape, Italy) as evidenced by mean DEof 68% and fine FPF of 83% as determined by Anderson Cascade Impactor(ACI). Particle size distribution for two batches of spray dried powderis depicted in FIG. 6. The particle size distribution included thefollowing values for the first batch: D₁₀ (um)=0.9; D₅₀ (um)=2.1; andD₉₀ (um)=4.6. The particle size distribution included the followingvalues for the second batch: D₁₀ (um)=0.8; D₅₀ (um)=1.9; and D₉₀(um)=4.1. Particle size distribution was very consistent across the twobatches. A scanning electron micrograph showing particle appearance isshown in FIG. 7.

Ingredients for producing a dry powder composition having approximately6.4% by weight cannabinoid active ingredient include leucine (2.9 g),inulin (1.0 g), HPMC (0.15 g), d-limonene (1.1 g), Plantamulse™ (0.4 g),supercritically extracted cannabis oil containing 90% THC (0.3 g), andwater. The emulsion (annex solution) was prepared in accordance with theprocess of Example 1.

A Production Minor (GEA Group, DE) with custom high efficiency cyclonewas used to generate and collect the powder. The equilibrium dryingcondition was established using de-ionized water. When stable operationwas achieved, the nozzle input was switched to annex (feedstock)solution. The solution was fed to the dryer until it was depleted andthen the nozzle was switched back to water for approximately 5 minutesto clear the system. The collector containing dry powder was exchangedfor a clean collector and the dryer was then shut down. The filledcollector was rapidly capped on removal to minimize exposure to roomhumidity. The filled collector was transferred into a low humidity glovebox purged with clean dry air or nitrogen where the powder wastransferable into other vessels for storage or into capsules and/orother unit dose packets.

EXAMPLE 4

A carbohydrate bulking agent was included in an oil extract-leucineformulation. The addition of trehalose as a carbohydrate bulking agentcan improve the chemical stability of dry-powder cannabinoidcompositions of the present disclosure. Additionally, trehalose and DSPCwere inserted in the powder formulation based on their inclusion in DPIproducts approved by the FDA, e.g TOBI® Podhaler™ (Novartis, AG).

Dry powder oil extract compositions suitable for pulmonary delivery wereproduced using a Mobile Minor (GEA Group, DE) spray dryer. Capsulesfilled with these powders (10 mg target) had an MMAD of 2.3 μm andexhibited excellent aerosol performance when actuated via the RS01inhaler (Plastiape, Italy) as evidenced by FPF of 93% and DE of 90%. Theparticle size distribution for the spray dried powder is depicted inFIG. 8. The particle size distribution included the following values:D₁₀ (um)=1.1; D₅₀ (um)=2.2; and D₉₀ (um)=4.2.

Ingredients for producing a dry powder composition having approximately12% by weight active ingredient include leucine (80%), trehalose (6.5%),DSPC (1.5%), and supercritically extracted oil (12%). Water andd-limonene were used as solvents. The emulsion (annex solution) wasprepared in accordance with the process of Example 1.

EXAMPLE 5

A carbohydrate bulking agent was included in a cannabinoid-leucineformulation. The addition of trehalose as a carbohydrate bulking agentcan improve the chemical stability of dry-powder cannabinoidcompositions of the present disclosure. Additionally, trehalose has beenincorporated in powder for pulmonary administration products approved bythe FDA, e.g TOBI® Podhaler™ (Novartis, AG).

Dry powder cannabinoid compositions suitable for pulmonary delivery wereproduced using a Mobile Minor (GEA Group, DE) spray dryer. These powdersexhibited very good aerosol performance when actuated via the RS01inhaler (Plastiape, Italy) as evidenced by mean DE of 68% and fine FPFof 83% as determined by Anderson Cascade Impactor (ACI operated at 28.3lpm). The particle size distribution for the spray dried powder isdepicted in FIG. 9. The particle size distribution included thefollowing values: D₁₀ (um)=0.5; D₅₀ (um)=2.7; and D₉₀ (um)=6.0.

Ingredients for producing a dry powder composition having approximately5% by weight cannabinoid active ingredient include leucine (47%),trehalose (47%), DSPC (1%), and supercritically extracted cannabiscrystals containing 99% CBD (5%). Water and d-limonene were used assolvents. The emulsion (annex solution) was prepared in accordance withthe process of Example 1.

What is claimed is:
 1. A method of manufacturing a flowable anddispersible powder, the method comprising: solubilizing a lipophilicsubstance and a phospholipid in a terpene to form a lipophilic mixture;adding at least one functional excipient to water to form an aqueoussolution in which the functional excipient is dissolved; after the atleast one functional excipient is completely dissolved, dispersing thelipophilic mixture into the aqueous solution using one or both of ahomogenizer or an ultrasonic device to form a coarse emulsion; treatingthe coarse emulsion with a microfluidizer to form a nanoemulsion; andspray drying the nanoemulsion to evaporate at least a portion of theterpene and substantially all of the water to form a dry powder forpulmonary administration in powder form, the dry powder being formedfrom solid particles comprising the lipophilic substance, the resultantdry powder having a mass median aerosol diameter (MMAD) between 0.5 and5 μm, and a fine particle fraction (FPF) and delivery efficiency (DE)greater than 60%.
 2. The method of manufacturing a flowable anddispersible powder of claim 1, wherein: the dry powder has a moisturecontent below about 10% by weight water.
 3. The method of manufacturinga flowable and dispersible powder of claim 1, wherein: the dry powderhas a tap density between about 0.1 g/cm³ and 0.6 g/cm³.
 4. The methodof manufacturing a flowable and dispersible powder of claim 1, wherein:the lipophilic substance comprises one or more of a cannabinoid, alphatocopherol, amphotericin B, atorvastatin, azithromycin, beclomethasone,budesonide, caspofungin, ciprofloxacin, clemastine, clofazimine,cyclosporine, dihydroergotamine, dronabinol, dutasteride, erythromycin,felodipine, fentanyl, flecainide, fluticasone furoate, fluticasonepropionate, furosemide, glycopyrronium, indacaterol, itraconazole,loxapine, mometasone, nimodipine, tacrolimus, tretinoin, vilanterol, orderivatives or analogues thereof.
 5. The method of manufacturing aflowable and dispersible powder of claim 1, wherein: the lipophilicsubstance is dispersed in an aqueous phase and the utility of alipophilic phase is to impart the MMAD, the FPF, and the DE to thespray-dried powder.
 6. The method of manufacturing a flowable anddispersible powder of claim 5, wherein: the lipophilic substancecomprises nicotine.
 7. The method of manufacturing a flowable anddispersible powder of claim 6, wherein: a plurality of emulsionscontaining separate drug substances are combined with the aqueoussolution and once spray dried, produce combination products.
 8. Themethod of manufacturing a flowable and dispersible powder of claim 1,wherein: separate drug substances are contained within the aqueoussolution and the mixture and once spray dried, produce combinationproducts.
 9. The method of manufacturing a flowable and dispersiblepowder of claim 8, wherein: a plurality of emulsions containing separatedrug substances are combined with the aqueous solution and once spraydried, produce combination products.
 10. The method of manufacturing aflowable and dispersible powder of claim 1, wherein: a plurality ofemulsions containing separate drug substances are combined with theaqueous solution and once spray dried, produce combination products. 11.The method of manufacturing a flowable and dispersible powder of claim1, wherein: the dry powder comprises between about 1% and 20% by weightof a cannabinoid.
 12. The method of manufacturing a flowable anddispersible powder of claim 11, wherein: the cannabinoid comprises atleast one of tetrahydrocannabinol (THC), tetrahydrocannabinolic acid(THCa), cannabidiol (CBD), cannabidiolic acid (CBDa), cannabinol (CBN),cannabichromene (CBC), or cannabigerol (CBG).
 13. The method ofmanufacturing a flowable and dispersible powder of claim 1, wherein: thedry powder further comprises one or more of a hydrophobic amino acid, adisaccharide, a oligosaccharide, a surfactant, an emulsifier, astabilizing additive, or a bulking agent.
 14. The method ofmanufacturing a flowable and dispersible powder of claim 13, wherein:the hydrophobic amino acid comprises one or more of tryptophan,tyrosine, leucine, trileucine, or phenylalanine.
 15. The method ofmanufacturing a flowable and dispersible powder of claim 13, wherein:the stabilizing additive comprises one or more of a non-ionic detergent,a nonionic block copolymer, an ionic surfactant, phospholipids,citrates, sorbitan laurate, polyglyceryl-4 laurate, or cyclicoligosaccharisdes.
 16. The method of manufacturing a flowable anddispersible powder of claim 1, wherein: the dry powder contains one ormore of hydroxypropylmethylcellulose (HPMC) or methylcellulose (MC). 17.The method of manufacturing a flowable and dispersible powder of claim1, wherein: the dry powder comprises one or more of lactose, mannitol,trehalose, raffinose, or maltodextrins.
 18. The method of manufacturinga flowable and dispersible powder of claim 1, wherein: the terpenecomprises one or more of d-limonene, other limonenes, or beta-myrcene.19. The method of manufacturing a flowable and dispersible powder ofclaim 1, wherein: the dry powder has a bulk density of between about0.05 g/cm³ and 0.3 g/cm³.
 20. The method of manufacturing a flowable anddispersible powder of claim 1, wherein: the MMAD of the resultant drypowder is between about 1 and 3 μm.
 21. A method of manufacturing aflowable and dispersible powder, the method comprising: solubilizing alipophilic substance and a phospholipid in a terpene to form alipophilic mixture; adding at least one functional excipient to water toform an aqueous solution in which the functional excipient is dissolved;after the at least one functional excipient is completely dissolved,dispersing the lipophilic mixture into the aqueous solution using one orboth of a homogenizer or an ultrasonic device to form a coarse emulsion;treating the coarse emulsion with one or both of the ultrasonic deviceor a high shear device to form a nanoemulsion; and spray drying thenanoemulsion to evaporate at least a portion of the terpene andsubstantially all of the water to form a dry powder for pulmonaryadministration in powder form, the dry powder being formed from solidparticles comprising the lipophilic substance, the resultant dry powderhaving a mass median aerosol diameter (MMAD) between 0.5 and 5 μm, and afine particle fraction (FPF) and delivery efficiency (DE) greater than60%.